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NM_000251.3(MSH2):c.2714C>T (p.Thr905Ile) AND Lynch syndrome

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Nov 20, 2023
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV003997168.2

Allele description [Variation Report for NM_000251.3(MSH2):c.2714C>T (p.Thr905Ile)]

NM_000251.3(MSH2):c.2714C>T (p.Thr905Ile)

Gene:
MSH2:mutS homolog 2 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
2p21
Genomic location:
Preferred name:
NM_000251.3(MSH2):c.2714C>T (p.Thr905Ile)
HGVS:
  • NC_000002.12:g.47482858C>T
  • NG_007110.2:g.84735C>T
  • NM_000251.3:c.2714C>TMANE SELECT
  • NM_001258281.1:c.2516C>T
  • NP_000242.1:p.Thr905Ile
  • NP_000242.1:p.Thr905Ile
  • NP_001245210.1:p.Thr839Ile
  • LRG_218t1:c.2714C>T
  • LRG_218:g.84735C>T
  • LRG_218p1:p.Thr905Ile
  • NC_000002.11:g.47709997C>T
  • NM_000251.1:c.2714C>T
  • NM_000251.2:c.2714C>T
  • p.T905I
Protein change:
T839I
Links:
dbSNP: rs267608022
NCBI 1000 Genomes Browser:
rs267608022
Molecular consequence:
  • NM_000251.3:c.2714C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258281.1:c.2516C>T - missense variant - [Sequence Ontology: SO:0001583]
Observations:
19

Condition(s)

Name:
Lynch syndrome
Identifiers:
MONDO: MONDO:0005835; MedGen: C4552100

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004829875All of Us Research Program, National Institutes of Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain Significance
(Nov 20, 2023) 		germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown19not providednot provided108544not providedclinical testing

Citations

PubMed

Methylation Tolerance-Based Functional Assay to Assess Variants of Unknown Significance in the MLH1 and MSH2 Genes and Identify Patients With Lynch Syndrome.

Bouvet D, Bodo S, Munier A, Guillerm E, Bertrand R, Colas C, Duval A, Coulet F, Muleris M.

Gastroenterology. 2019 Aug;157(2):421-431. doi: 10.1053/j.gastro.2019.03.071. Epub 2019 Apr 15.

PubMed [citation]
PMID:
30998989

Massively parallel functional testing of MSH2 missense variants conferring Lynch syndrome risk.

Jia X, Burugula BB, Chen V, Lemons RM, Jayakody S, Maksutova M, Kitzman JO.

Am J Hum Genet. 2021 Jan 7;108(1):163-175. doi: 10.1016/j.ajhg.2020.12.003. Epub 2020 Dec 23.

PubMed [citation]
PMID:
33357406
PMCID:
PMC7820803
See all PubMed Citations (4)

Details of each submission

From All of Us Research Program, National Institutes of Health, SCV004829875.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided19not providednot providedclinical testing PubMed (4)

Description

This missense variant replaces threonine with isoleucine at codon 905 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A methylation tolerance assay found this variant had tolerance consistent with a neutral variant in colorectal cancer cells (PMID: 30998989), and this variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in family affected with Lynch syndrome associated cancers (PMID: 30998989). In a large breast cancer case-control study, this variant was observed in one affected individual and two healthy individuals (PMID: 33471991). This variant has been identified in 23/282122 chromosomes (16/10350 Ashkenazi Jewish chromosomes) in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown108544not providednot provided19not providednot providednot provided

Last Updated: May 7, 2024